Synthesis of optically active 1,4-dioxane nucleotide analogs

Article abstract of DOI:10.1080/00397910802326513

Optically active nucleotide analogs were prepared that were composed of a 1,4-dioxane ring as the sugar analog to which either uracil or adenine attached together with two carboxylic ester groups, to be used as vehicles for formation of oligomers. The chiral 1,4-dioxane moiety was constructed from dimethyl L-tartrate via the corresponding (2R,3R)-dimethyl 2-O-allyl-tartrate. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802326513

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Synthesis of Optically Active
1,4-Dioxane Nucleotide
Analogs
Qiang Yu a , Stefanie Kaffarnik b & Per Carlsen a
a Department of Chemistry , Norwegian University of
Science and Technology , Trondheim, Norway
b Department of Chemistry , University of Hamburg ,
Hamburg, Germany
Published online: 31 Oct 2008.
To cite this article: Qiang Yu , Stefanie Kaffarnik & Per Carlsen (2008) Synthesis
of Optically Active 1,4-Dioxane Nucleotide Analogs, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:23,
4250-4264, DOI: 10.1080/00397910802326513
To link to this article: http://dx.doi.org/10.1080/00397910802326513
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Synthetic Communications1, 38: 4250–4264, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802326513
Synthesis of Optically Active 1,4-Dioxane
Nucleotide Analogs
Qiang Yu,1 Stefanie Kaffarnik,2 and Per Carlsen1
1Department of Chemistry, Norwegian University of Science and
Technology, Trondheim, Norway
2Department of Chemistry, University of Hamburg,
Hamburg, Germany
Abstract: Optically active nucleotide analogs were prepared that were composed
of a 1,4-dioxane ring as the sugar analog to which either uracil or adenine
attached together with two carboxylic ester groups, to be used as vehicles for for-
mation of oligomers. The chiral 1,4-dioxane moiety was constructed from
dimethyl L-tartrate via the corresponding (2R,3R)-dimethyl 2-O-allyl-tartrate.
Keywords: Chiral pool, chiral synthesis, cyclization, nucleotide analogs, oxygen
heterocycles
INTRODUCTION
Nucleoside, nucleotide, and oligonucleotide analogs are compounds of
increasing interest and represent a fast-growth area. Polynucleotides
are the biopolymers responsible for the transfer of genetic information
in all living cells and for the translation of this information for the speci-
fic synthesis of proteins required in the cells. Synthesis of DNA and RNA
analogs are therefore of interest as model systems for the investigation of
relationships between structure and activity and have found applications
as functional materials[1] and as enzyme mimics.[2] Examples are known
where such compounds exhibit antiviral activity.[3] This is important in
Received March 27, 2008.
Address correspondence to Per Carlsen, Department of Chemistry, Norwegian
University of Science and Technology, 7491 Trondheim, Norway. E-mail: per.
carlsen@chem.ntnu.no
4250

1,4-Dioxane Nucleotide Analogs
4251
light of the increasing number of examples of drug resistance. Some
nucleoside analogs such as 30-azido-30-deoxythy-midine (AZT, Retrovir)
and 2030-thiacytidine (3TC, Epivir) are currently approved for the treat-
ment of AIDS and are believed to work by termination of replicating
DNA chains. Polymers with grafted nucleoside analogs are attracting
increasing interest as agents for nonviral gene delivery. This was recently
reviewed by Eliyahu et al.[4]
RESULTS AND DISCUSSION
Our objective was to prepare optically active nucleotide analogs, consist-
ing of the substituted relatively flexible 1,4-dioxane system as the equiva-
lent to the sugar counterpart in the natural nucleotides and substituted
with either of the complementary bases uracil or adenine. In addition
two ester groups will function as the vehicle for subsequent condensation
into oligonucleotide analogs. For this reason they were classified as
nucleotide analogs. A representative structure is shown in Fig. 1. We
are interested in synthesis of systems that do not contain the components
known from biochemistry but will apply the structural and reaction
principles known from nature.
Nucleoside analogs containing dioxolane rings have previously been
synthesized,[5,6] and some were reported to display broad antiviral and
antineoplastic activities.[7] Wilds and coworkers have in a series of papers
reported studies of polynucleotides in which the natural pentose sugars
found in DNA and RNA were replaced by various hexoses[8] or furanosyl
heterocycles.[9]
The optical activity was introduced through the application of
L-tartaric acid, which is an inexpensive and readily available chiral pool
starting material. Construction of the dioxane moiety was first prepared
the monoallylether of (2R,3R)-dimethyl tartrate by the reaction of
dimethyl tartrate with allyl bromide in the presence of silver oxide,[10]
yielding product 1, usually in good yields, (Scheme 1). This transforma-
tion was, however, difficult to reproduce, as yields depended on the
Figure 1. Optically active uracil and adenine nucleotide analogs.

4252
Q. Yu, S. Kaffarnik, and P. Carlsen
Scheme 1. Synthesis of (2R,3R)-dimethyl 2-O-allyl-tartrate, 1.
quality of the silver oxide reagent. Typically, the commercial reagent
gave low yields only, while freshly prepared silver oxide usually resulted
in satisfactory yields, though still an occasional inconvenient batch
dependency was observed. Therefore 1 was alternatively prepared used
the method previously reported by Nagashima and Ohno[11] in which
(2R,3R)-dimethyl tartrate was reacted dibutyltin oxide with azeotropic
removal of water to form stannylene acetal 2, and subsequently reacted
with allyl bromide in the presence of cesium fluoride to give 1 in con-
sistently good isolated yield. Ozonolysis of 1 gave aldehyde 3, which
spontaneously cyclized to afford the dioxane hemiacetal 4. NMR data
indicated the product consisted of 3 and 4 as a 2:98 mixture. The hemi-
acetal 4 consisted of both of the anomers, which were converted into
the corresponding acetates, dimethyl (2R,3R)-5-acetoxy-1,4-dioxane-
2,3-dicarboxylate, 5, by acetylation with acetic anhydride in pyridine.[12]
See Scheme 2.
Compound 5 was next converted to the nucleotide analog 6 using the
¨
Vorbruggen’s procedure,[13] by coupling 5 with silylated uracil, 7, in the
presence of trimethylsilyl triflate (TMSOTf). The product was isolated
as a diastereomeric mixture of anomers 6a and 6b in a 2:1 ratio
Scheme 2. Synthesis of (2R,3R)-dimethyl 5-acetoxy-1,4-dioxane-2,3-dicarboxy-
late, 5.

1,4-Dioxane Nucleotide Analogs
4253
Scheme 3. Synthesis of the dimethyl 5-(1-uridyl)-1,4-dioxan-2,3-dicarboxylate, 6.
(Scheme 3). Recrystallization of the 6a=6b mixture from acetonitrile gave
the pure anomer 6a.
All attempts to prepare the corresponding 9-adenyl substituted
nucleotide analog 8 using a similar reaction scheme failed. Thus, when
the anomeric mixture of acetates 5 was coupled with silylated adenine,
9, in the presence of TMSOTf, the only isolated product was the corre-
sponding 7-adenyl-substituted nucleotide analogs 10a,b, (Scheme 4).
The anomers were not separated.
To obtain the 9-adenyl-substituted nucleotide analog 8, silylated N-6-
benzoyl adenine, 11, was coupled with 5, and gave the N-9 substituted
adenine analoge, 12. All attempts to deprotect 12 by treatment with
sodium methoxide[14] failed to give product 8. Only intractable materials
were isolated, (Scheme 5).
Instead acetate 5 was converted into the corresponding bromide 13
by reacting 5 with HBr in acetic acid.[15] Bromide 13 was subsequently
reacted with silylated adenine 9 in the presence of tetrabutyl ammonium
fluoride in dry THF,[16] yielding the 9-adenyl-substituted product 8,
Scheme 4. Formation of dimethyl 5-(7-adenyl)-1,4-dioxan-2,3-dicarboxylate, 10.

4254
Q. Yu, S. Kaffarnik, and P. Carlsen
Scheme 5. Synthesis of dimethyl 5-(benzamido-9H-purin-9-yl)-1,4-dioxan-2,3-
dicarboxylate, 12.
Scheme 6. A byproduct was isolated and assigned the structure of the cor-
responding 3-Adenyl substituted compound 14. These products were
separated by column chromatography; however, in our hands the chro-
matographic separation of anomers 8a and 8b failed.
The assignment of the structures of regioisomers 8, 10, and 14 were
based on heteronuclear multiple bond correlation (HMBC) investiga-
tions. The chemical shifts of the C5-carbon atoms were readily assigned
due to the connectivity. Thus, the chemical shift of the C5-carbons
appeared at lower d values in the 13C NMR spectra than the other
carbons in the adenine ring (Scheme 6).
Scheme 6. Formation of dimethyl 9-adenyl-1,4-dioxane-2,3,-dicarboxylate, 8,
and the 3-adenyl isomer 14.

1,4-Dioxane Nucleotide Analogs
4255
Figure 2. Adenine nucleotide analogs 8, 18, and 14.
3
For the N-7 regioisomer 10, a JC-H coupling was observed between
C5 and the anomeric proton HA. In the cases of the N-9 regioisomer 8
3
and N-3 regioisomer 14, JC-H couplings were not observed between
the carbon C5 and the anomeric protons HA. Isomers 8, 10, and 14 all
3
exhibited JC-H couplings observed between carbon C5 and proton HC.
3
A JC-H coupling was observed for 8 between the anomeric carbon and
HC, which was not the case for product 14, which however exhibited a
3JC-H coupling between the anomeric carbon and HB. The structure of
product 12 was similarly confirmed to be the protected 9-substituted
adenine (Fig. 2).
The anomeric structures were assigned based on nuclear Overhauser
enhancement spectroscopy (NOESY). Nuclear Overhauser effects (NOE)
were observed for protons HA and HB when the R-substituent was
equatorial, but not when the R-group was axial, (Fig. 3). The anomeric
ratios were determined by integration of the appropriate proton NMR
signals.
Figure 3. Structures of anomers.

4256
Q. Yu, S. Kaffarnik, and P. Carlsen
EXPERIMENTAL
NMR spectra were recorded on Bruker Avance DPX 300 or DPX 400
instruments. Chemical shifts are reported in ppm relative to TMS as the
internal standard in CDCl3 or [D6]DMSO (2.50 ppm for 1H and
39.99 ppm for 13C). Structural assignments are based on 2D-spectra of
correlation spectroscopy (COSY), heteronuclear single quantum coher-
ence (HSQC), heteronuclear multiple bond correlation (HMBC),
NOESY, and distortionless enhancement by polarization transfer
(DEPT-135). EI-mass spectra were measured on a Finnigan MAT 95XL
spectrometer. IR spectra were recorded on a Thermo Nicolet FT-IR
Nexus spectrometer with a Smart Endurance reflection cell. Silica gel Kie-
selgel 60 G (Merck) was used for flash chromatography. For ozonolysis an
OZ 500 ozone generator produced by Fischer Technology was used. Opti-
cal rotations were measured using a Perkin-Elmer model 341 polarimeter.
(2R,3R)-Dimethyl 2-O-Allyl-tartrate, 1
Method 1
A solution of dimethyl-L-tartrate (44.5 g, 0.25 mol) and allyl bromide
(26 mL, 0.31 mol) in diethylether (1000 mL) was gently refluxed in the
dark for 10 min. Silver oxide (Ag2O, 58.2 g, 0.251 mol) was then added
in three portions. The resulting mixture was refluxed for 2 h and stirred
2 days at room temperature. The resulting reaction mixture was filtered,
was and the filtrate was concentrated under reduced pressure. The cruÀd2e
product was then distillated under vacuum (bp 102–105 ꢀC, 1 Â 10
mbar) yielding 45.7 g, 84% of the pure product.
Method 2
To the solution of dimethyl-L-tartrate (7.21 g, 40 mmol) in 130 mL of
toluene was added dibutyltin oxide (10.12 g, 40 mmol), and the resulting
mixture was heated to reflux 2 h, removing water by azeotropic distilla-
tion. The solution was evaporated to complete dryness in vacuo to give
the stannylene acetal of the dialkyl tartrate, which was used for the fol-
lowing step without purification. To the stannylene acetal was added
cesium fluoride (8.40 g, 54.7 mmol), and the resulting mixture was dried
at 40ꢀC in vacuo for 1–2 h. To the resulting mixtures was then added
80 mL of dry DMF together with allyl bromide (5.92 g, 48.9 mmol),
and the resulting suspension was stirred for 2 days at room temperature.
Then DMF was removed under vacuum, and the residue was extracted

1,4-Dioxane Nucleotide Analogs
4257
with ethyl acetate. The organic layer was dried over anhydrous sodium
sulfate, concentrated, and purified by silica gel column chromatography
using hexane–EtOAc (1:2) as the eluent. The product 1 was obtained as a
colorless oil, 6.10 g, 70% yield, which exhibited the following spectrocopic
properties: 1H NMR (CDCl3, 400 MHz): d ¼ 3.09 (d, J ¼ 8.8 Hz, 1H,
OH), 3.82 (s, 3H, CO2CH3), 3.83 (s, 3H, CO2CH3), 3.90–3.96 (m, 1H,
OCH2), 4.28–4.33 (m, 1H, OCH2), 4.34 (d, J ¼ 2.4 Hz, 1H, CHOCH2),
4.62 (dd, J ¼ 2.4 Hz, 8.8 Hz, 1H, CHOH), 5.20–5.27 (m, 2H, CH ¼ CH2),
5.76–5.86 (m, 1H, CH¼CH2) ppm. 13C NMR [CDCl3, 100 MHz]:
d ¼ 52.6, 53.0, 72.4, 72.6, 78.4, 118.7, 133.5, 170.0, 171.7 ppm. MS
(70 eV) m=z: 219 (Mþ þ 1), 159 (Mþ-COOCH3), 129 (Mþ-CHOH-
COOCH3). IR (neat): 3487, 2955, 1738, 1436, 1101 cmꢀ1
.
(2R,3R)-Dimethyl 5-Hydroxy-1,4-dioxane-2,3-dicarboxylate, 4
Compound 1 (24.0 g, 0.11mol) was dissolved in 500 mL of a mixture of
methanol=dichloromethane (1:4) and cooled toꢀ76ꢁC. A stream of O3
waspassedthroughthissolutionuntil itturnedapersistent bluecolor. Excess
ozone was flushed with a stream of oxygen or nitrogen. Then a solution of
dimethyl sulfide (8.14 g, 0.13mol) in dichloromethane (50 mL) was added
dropwise at room temperature, and the resulting mixture was stirred over-
night. The solvent was removed under reduced pressure, and the residue
was purified by flash chromatography using ethyl ether=n-hexane (9:1) as
the eluent to give the product as a colorless oil (11.8 g, 48.7%). The anomeric
ration 4b=4a was determined to 2:1. The product exhibited the following
spectroscopic properties: 1H NMR (CDCl3, 400 MHz): (axial product, 4b):
d ¼ 5.25 (t, J ¼ 2.8 Hz, 1H, CH-OH), 4.93 (d, J ¼ 6.8 Hz, 1H, CH-COOMe),
4.46 (d, J ¼ 6.8 Hz, 1H, CH-COOMe), 3.76–3.83 (m, 2H, OCH2-CH-OH),
3.811 (s, 3H, CH3-COO), 3.801 (s, 3H, CH3-COO). Equitorial product, 4a:
d ¼ 5.06 (dd, J ¼ 7.2 Hz, 2.8 Hz, 1H, CH-OH), 4.53 (d, J ¼ 7.8 Hz, 1H,
CH-COOMe), 4.33 (d, J ¼ 7.8 Hz, 1H, CH-COOMe), 4.0 (dd, J ¼ 11.6 Hz,
2.8 Hz, 1H, OCH2-CH-OH), 3.797 (s, 3H, CH3-COO), 3.794 (s, 3H, CH3-
COO), 3.45 (dd, J ¼ 11.6 Hz, 7.2 Hz, 1H, OCH2-CH-OH) ppm. 13C-NMR
(CDCl3,100MHz,): d ¼ 169.1, 168.6, 168.3, 91.5, 88.7, 74.2, 74.1, 74.0,
70.1, 68.5, 67.7, 52.83, 52.80, 52.7 ppm. IR (neat): 3450, 2956, 1735,
1438cmꢀ1. MS (70 eV) m=z: 220.1, 162.1, 143.1, 113.0, 103.1 cmꢀ1. Elem.
anal. calc. for C8H12O7: C, 43.64; H, 5.49. Found: C, 43.42; H, 5.41.
(2R,3R)-Dimethyl 5-Acetoxy-1,4-dioxane-2,3-dicarboxylate, 5
To an ice-cold stirred solution of 4 (5.13 g, 23 mmol) in pyridine (50 mL)
was dropwise added acetic anhydride (6.76 g, 66 mmol), and the reaction

4258
Q. Yu, S. Kaffarnik, and P. Carlsen
mixture was stirred at room temperature overnight. To the solution was
added methanol (10 mL) at 0–5 ꢁC, stirred half an hour at room tempera-
ture, and then concentrated under reduced pressure. The residue was dis-
tilled to afford 5.25 g, 87.1% of the product as slightly yellow syrup with
bp 138–142ꢁC, 1 ꢂ 10ꢀ3mbar. The ratio of axial to equatorial acetoxy
groups was 1:1.2. The product exhibited the following spectroscopic
properties: 1H NMR (CDCl3, 400 MHz): (equatorial product, 5a):
d ¼ 5.91 (dd, J ¼ 2.6 Hz, 5.0 Hz, 1H, CH-OAc), 4.66 (d, J ¼ 5.6 Hz, 1H,
CH-COOMe), 4.64 (d, J ¼ 5.6 Hz, 1H, CH-COOMe), 4.09 (dd, 1H,
J ¼ 12 Hz, 2.6 Hz OCH2-CH-OAc), 3.64 (dd, 1H, J ¼ 12 Hz, 5.0 Hz,
OCH2-CH-OAc). 3.83, 3.813, 3.812, 3.798 [s, 3H ꢂ 4, CH3-COO (both
axial and equatorial products), 3H, OCOCH3] ppm. Axial product 5b]:
d ¼ 6.07 (t, J ¼ 2.2 Hz, 1.4 Hz, 1H, CH-OAc), 4.73 (d, J ¼ 9.0 Hz, 1H,
CH-COOMe), 4.40 (d, J ¼ 9.0 Hz, 1H, CH-COOMe), 3.98 (dd,
J ¼ 12.6 Hz, 1.4 Hz, 1H, OCH2-CH-OAc), 3.91(dd, J ¼ 12.6 Hz, 2.2 Hz,
1H, OCH2-CH-OAc), 2.16(s, 3H, OCOCH3) ppm. 13C NMR (CDCl3,
100 MHz): d ¼ 169.4, 169.1, 168.5, 168.3, 167.7, 167.6, 88.1, 87.8, 75.1,
72.9, 72.7, 70.6, 67.0, 65.3, 53.0, 52.95, 52.91, 52.89, 21.1, 20.9 ppm. IR
(neat): 2957, 1740, 1438 cmꢀ1. MS (70 eV) m=z: 262.2, 203.1, 191.1,
175.1, 143.1, 103.1. Elem. anal. calcd. for C10H14O8: C, 45.81; H, 5.38.
Found: C, 45.20; H, 5.16.
(2R,3R,5S)-Dimethyl 5-(1-Uridyl)-1,4-dioxan-2,3-dicarboxylate, 6a, and
(2R,3R,5R)-Dimethyl 5-(1-Uridyl)-1,4-dioxan-2,3-dicarboxylate, 6b
A mixture containing uracil (5.6 g, 50 mmol), ammonium sulfate (0.67 g,
5 mmol), and 100 mL hexamethyldisilazane (HMDS) was refluxed over-
night. After removing the solvent under reduced pressure, the residue
(7) was dissolved into 80 mL of dry CH3CN, and a solution of 5 (6.5 g,
25 mmol) in 20 mL of dry CH3CN was added. The solution was cooled
to ꢀ10 ꢁC, and TMSOTf (5 mL, 27.5 mmol) was added. The resulting
mixture was then stirred overnight at room temperature. To the reaction
mixture was then added 160 mL of CH2Cl2, and it was quenched with
saturated aqueous NaHCO3 solution. The aqueous layer was extracted
with 3 ꢂ 50 mL of CH2Cl2. The combined organic phase was dried over
anhydrous MgSO4 and filtered; and the solvent evaporated. The residue
was purified by column chromatography (SiO2) using ethyl acetate as the
eluent to give a mixture of 6a and 6b (2.7 g, 35%). The ratio of axial and
equatorial product, 6b=6a, was 1:2. Crystallization from CH3CN
at ꢀ10ꢁC provided 6a (0.83 g, 11%). The product exhibited the following
1
spectroscopic properties; H NMR ([D6]DMSO, 400 MHz): (axial pro-
duct, 6b): d ¼ 7.55 (d, J ¼ 8 Hz, 1H, CH ¼ CH-N-), 6.09 (dd, J ¼ 8.4 Hz,

1,4-Dioxane Nucleotide Analogs
4259
4.0 Hz, 1H, OCH2-CH-N-), 5.66 (d, J ¼ 8 Hz, 1H, CH¼CH-N-), 5.09 (d,
J ¼ 2.0 Hz, 1H, CH-COOMe), 4.82 (d, J ¼ 2.0 Hz, 1H, CH-COOMe),
3.85–3.92 (m, 1H, OCH2-CH-N), 3.65–3.72 (m, 1H, OCH2-CH-N),
3.79, 3.76 (s, 3H ꢂ 2, CH3-COO) ppm. 13C NMR ([D6]DMSO
100 MHz,): d ¼ 168.7, 168.6, 162.8, 150.0, 140.5, 102.3, 74.1, 72.9, 71.2,
63.1, 52.7, 52.6 ppm. Equatorial product, 6a: d ¼ 7.71 (d, J ¼ 8 Hz, 1H,
CH¼CH-N-), 5.85 (dd, J ¼ 9.6 Hz, 3.2 Hz, 1H, OCH2-CH-N-), 5.71 (d,
J ¼ 8 Hz, 1H, CH¼CH-N-), 4.70 (d, J ¼ 9.6 Hz, 1H, CH-COOMe), 4.37
(d, J ¼ 9.6 Hz, 1H, CH-COOMe), 3.96 (dd, J ¼ 11.6 Hz, 3.2 Hz, 1H,
OCH2-CH-N), 3.88 (dd, J ¼ 11.6 Hz, 9.6 Hz, 1H, OCH2-CH-N), 3.70,
3.69 (s, 3H ꢂ 2, CH3-COO) ppm. 13C NMR ([D6]DMSO, 100 MHz,):
d ¼ 167.1, 166.6, 162.8, 149.9, 140.6, 102.3, 77.2, 75.5, 73.9, 65.5, 52.4,
52.3 ppm. IR (neat): 3598, 3031, 1747, 1708, 1666, 1440 cmꢀ1. MS
(70 eV) m=z: 314.2, 255.1, 203.1, 175.1, 143.1, 113.1. Elemental analysis
calculated for C12H14N2O8: C,45.86; H, 4.49; N, 8.91. Found: C, 45.58;
25
H, 4.50; N, 8.39. ½aꢃD ¼ ꢀ16:9 ꢁ (c¼3.14, chloroform).
(2R,3R,5S)-Dimethyl 5-(7-Adenyl)-1,4-dioxan-2,3-dicarboxylate, 10a, and
(2R,3R,5R)-Dimethyl 5-(7-adenyl)-1,4-dioxan-2,3-dicarboxylate, 10b
These products were obtained using a similar procedure as described for
the synthesis of the uracil system 6a, b, using adenine (1.37g, 10.1 mmol),
ammonium sulfate (140 mg, 1.1 mmol), and 45 mL hexamethyldisilazane
(HMDS), providing 9, which together with 5 (0.94 g, 3.6 mmol) and
TMSOTf (0.7 mL, 3.9 mmol) in dry dichloroethane gave 10a, 10b. The
crude product was purified by flash chromatography (SiO2) using a mix-
ture of CH2Cl2= CH3OH (9:1) as the eluent to give a mixture of 10a and
10b (0.42 g, 35.1%). The ratio of axial to equatorial substituted dioxane
was determined to 0.8:1. Spectroscopic properties: 1H NMR
([D6]DMSO, 400 MHz): (axial product, 10b) d ¼ 8.47 (s, 1H, C8-H in ade-
nine), 8.25 (s, 1H, C2-H in adenine), 6.97 (s, 2H, NH2), 6.25 (dd, J ¼ 7 Hz,
3 Hz, 1H, CH-adenine), 4.96 (d, J ¼ 3.8Hz, 1H, CH-COOMe), 4.89 (d,
J ¼ 3.8 Hz, 1H, CH-COOMe), 4.26 (dd, 1H, J ¼ 12.0 Hz, 3 Hz OCH2-
CH-adenine), 4.22 (dd, 1H, J ¼ 12.0 Hz, 3 Hz OCH2-CH-adenine),
d3.791, 3.785 (s, 3H ꢂ 2, CH3-COO-) ppm. Equitorial product, 10a:
d ¼ 8.46 (s, 1H, C8-H in adenine), 8.26 (s, 1H, C2-H in adenine), 6.22
(dd, J ¼ 9 Hz, 3 Hz, 1H, CH-adenine), 4.99 (d, J ¼ 8.8 Hz, 1H, CH-
COOMe), 4.50 (d, J ¼ 8.8 Hz, 1H, CH-COOMe), 4.46 (dd, 1H,
J ¼ 11.7 Hz, 7 Hz OCH2-CH-adenine), 4.11 (dd, 1H, J ¼ 11.7 Hz, 9 Hz
OCH2-CH-adenine), 3.74, 3.62 (s, 3H ꢂ 2, CH3-COO-) ppm. 13C NMR
([D6]DMSO, 100 MHz): d ¼ 168.1, 167.8, 167.0, 166.7, 160.04, 159.96,
152.8, 152.7, 151.3, 151.2, 143.9, 143.6, 110.2, 110.0, 78.7, 76.2, 74.7,

4260
Q. Yu, S. Kaffarnik, and P. Carlsen
73.9, 72.2, 71.6, 66.4, 63.5, 52.8, 52.6, 52.4, 52.3 ppm. IR (neat): 3434,
3347, 2955, 1739, 1625, 1599, 1555, 1690, 1269, 1221, 1124, 1095,
1011 cmꢀ1. Elem. anal. calcd. for C13H15N5O6: C, 46.29; H, 4.48; N,
20.76. Found C, 45.89; H, 4.15, N 20.38.
(2R,3R,5S)-Dimethyl 5-(Benzamido-9H-purin-9-yl)-1,4-Dioxan-2,3-di-
carboxylate, 12a, and (2R,3R,5R)-Dimethyl 5-(Benzamido-9H-purin-9-yl)-
1,4-dioxan-2,3-dicarboxylate, 12b
These products were obtained using a similar procedure as described for
the synthesis of the uracil system 6a,b, using 6-benzamido-purine (5.6 g,
50 mmol) and (NH4)2SO4 (0.67 g, 5 mmol) and HMDS (100 mL) and
coupled with 5 (6.5 g, 25 mmol) in 20 mL of dry CH3CN with TMSOTf
(5 mL, 27.5 mmol). After workup, the crude product was purified by flash
chromatography (SiO2) using ethyl acetate as the eluent, to afford the
diastereomeric mixture of 12a,b (0.25 g, 11%). Compound 12b was
further isolated by recrystallization from CH3CN. The product exhibited
1
a 12ab=12b ratio of 2:1 and the following spectroscopic properties: H
NMR ([D6]DMSO, 400 MHz): (axial product, 12b) d ¼ 12.64 (brs, 1H,
N-H), 8.47 (s, 1H, C-H in Adenine), 8.05–8.28 (m, 2H, C-H in adenine
and Ar-H), 7.48–7.59 (m, 4H, Ar-H), 7.05 (brs, 1H, CH-purine ring),
5.29 (d, J ¼ 2 Hz, 1H, CH-COOMe), 4.94 (d, J ¼ 2 Hz, 1H, CH-COOMe),
4.11 (d, 2H, J ¼ 6.4 Hz, OCH2-CH-purine ring), 3.84, 3.78 (s, 3H ꢂ 2,
CH3-COO-) ppm. 13C NMR ([D6]DMSO, 100 MHz): d ¼ 173.7, 168.6,
168.5, 146.7, 143.4, 142.7, 136.5, 131.8, 129.1, 128.0, 75.7, 73.2, 71.3,
64.0, 52.6, 52.6 ppm. IR (neat): 3135, 3061, 2957, 1741, 1634, 1596,
978, 859, 761 cmꢀ1. MS (70 eV) m=z: 441.4, 382.3, 240.2, 224.2, 202.1,
105.1, 77.1. Elem. anal. calcd. for C20H19N5O7: C, 54.42;H, 4.34; N,
15.87. Found: C, 54.10; H, 4.13; N, 15.99.
(2R,5R,6S)-Dimethyl 5-Bromo-1,4-dioxane-2,3-dicarboxylate, 13a, and
(2R,5R,6R)-Dimethyl 5-Bromo-1,4-dioxane-2,3-dicarboxylate, 13b
To a solution of 2.40 g of 4 in 50 mL of dichloromethane was dropwise
added 10 mL of a 33% HBr solution in acetic acid at 0ꢁC, and the mixture
was stirred overnight and then poured into 50 mL of ice water. The
organic layer was washed with 50 mL of saturated NaHCO3 solution
and 30 mL saturated NaCl solution and finally dried over anhydrous
MgSO4. The solvent was removed to leave crude 13 as a light brown solid
(1.85 g, 71.4%), which was used in the subsequent step without further
purification. The spectroscopic properties indicated a 3:2 axial to

1,4-Dioxane Nucleotide Analogs
4261
1
equatorial ratio. H NMR ([D6]DMSO, 400 MHz): (axial product 13b)
d ¼ 5.03 (dd, J ¼ 4.8 Hz, 2.6 Hz, 1H, CH-Br), 4.80 (d, J ¼ 5.4 Hz, 1H,
CH-COOMe), 4.47 (d, J ¼ 5.4 Hz, 1H, CH-COOMe), 3.63 (dd, 1H,
J ¼ 11.6 Hz, 2.6 Hz OCH2-CH-Adenine), 4.22 (dd, 1H, J ¼ 12.0 Hz,
3 Hz OCH2-CH-adenine), 3.791, 3.785(s, 3H ꢂ 2, CH3-COO-) ppm. Equi-
torial product, 13a: d ¼ 8.46 (s, 1H, C8-H in adenine), 8.26 (s, 1H, C2-H in
adenine), 6.22 (dd, J ¼ 9 Hz, 3 Hz, 1H, CH-adenine), 4.99 (d, J ¼ 8.8 Hz,
1H, CH-COOMe), 4.50 (d, J ¼ 8.8 Hz, 1H, CH-COOMe), 4.46 (dd, 1H,
J ¼ 11.7 Hz and 7 Hz OCH2-CH-Adenine), 4.11 (dd, 1H, J ¼ 11.7 Hz,
9 Hz OCH2-CH-adenine), 3.74, 3.62 (s, 3H ꢂ 2, CH3-COO-) ppm. 13C-
NMR ([D6]DMSO, 100 MHz,): d ¼ 168.1, 167.8, 167.0, 166.7, 160.0,
159.9, 152.8, 152.7, 151.3, 151.2, 143.9, 143.6, 110.2, 110.0, 78.7, 76.2,
74.7, 73.9, 72.2, 71.6, 66.4, 63.5, 52.8, 52.6, 52.4, 52.3 ppm. IR (neat):
2957, 1749, 1434, 1218, 1132 cmꢀ1. MS (70 eV) m=z: 284.1, 282.1,
252.1, 250.1, 225.1, 223.1, 203.2, 175.2, 143.2, 115.2.
(2R,5R,6S)-Dimethyl 5-(9-Adenyl)-1,4-dioxane-2,3-dicarboxylate, 8a, and
(2R,5R,6R)-Dimethyl 5-(9-Adenyl)-1,4-dioxane-2,3-dicarboxylate, 8b
A mixture of adenine (2.77 g, 10.5 mmol), ammonium sulfate (162 mg,
1.2 mmol), and 100 mL hexamethyldisilazane (HMDS) was refluxed over-
night. After removing the solvent under reduced pressure, the residue was
dissolved into 20 mL of dry THF and then heated to reflux, providing 9.
The mixture was added 0.35 mL of a 1.0 M solution of Bu4NF in THF.
Then compound 13 (3.4 g, 12 mmol) in 25 mL of dry THF was added,
and the reaction mixture was refluxed for 8 h and then cooled to room
temperature. The mixture was diluted with 100 mL of dichloromethane
and washed with 2 ꢂ 40 mL of water. The organic layer was dried over
anhydrous MgSO4 and filtered, and the solvent was evaporated. The resi-
due was purified by flash chromatography (SiO2) using CH2Cl2=CH3OH
(9:1) as the eluent to afford 8 (0.55 g, 13.6%) as a mixture of the anomers
together with the (2R,5R,6S)-dimethyl 5-(3-adenyl)-1,4-dioxane-2,3-
dicarboxylate, 14 (0.76 g, 18.8%). The axial product 8b exhibited the fol-
1
lowing spectroscopic properties: H NMR (CDCl3, 400 MHz): d ¼ 8.38
(s, 1H, C8-H in adenine), 8.25 (s, 1H, C2-H in adenine), 6.38 or 6.34
(br. s, 2H, NH2), 6.42 (dd, J ¼ 6.8 Hz, 3.6 Hz, 1H, CH-Adenine), 4.87
(d, J ¼ 4.4 Hz, 1H, CH-COOMe), 4.77 (d, J ¼ 4.4 Hz, 1H, CH-COOMe),
4.50 (dd, 1H, J ¼ 12.4 Hz, 6.8 Hz, OCH2-CH-adenine), 4.18 (dd, 1H,
J ¼ 12.4 Hz, 3.6 Hz OCH2-CH-adenine), 3.90, 3.85 (s, 3H ꢂ 2, CH3-
COO-) ppm. Equitorial product, 8a: d ¼ 8.36 (s, 1H, C8-H in adenine),
8.10 (s, 1H, C2-H in adenine), 6.38 or 6.34 (dd, J ¼ 9.2 Hz, 3.2 Hz, 1H,
CH-adenine), 4.71 (d, J ¼ 8.6 Hz, 1H, CH-COOMe), 4.53 (d, J ¼ 8.4 Hz,

4262
Q. Yu, S. Kaffarnik, and P. Carlsen
Hz, 1H, CH-COOMe), 4.31 (dd, 1H, J ¼ 12 Hz, 3.2 Hz OCH2-CH-ade-
nine), 4.14–4.19 (m, OCH2-CH-adenine), 3.84, 3.73 (s, 3H ꢂ 2, CH3-
COO-) ppm. 13C NMR (CDCl3 (100 MHz): d ¼ 168.2, 186.1, 167.2,
166.7, 155.1, 154.9, 152.5, 152.2, 149.7, 149.5, 139.2, 138.6, 119.1, 77.5,
75.8, 74.5, 72.2, 67.2, 65.2, 53.06, 53.04, 52.93, 52.88 ppm. IR (neat):
3326, 3169, 2957, 1744, 1638, 1597, 1125 cmꢀ1. MS (70 eV) m=z: 337.1,
306.1, 278.1, 204.0, 173.0, 135.1. Elem. anal. calcd. for C13H15N5O6: C
46.29; H, 4.48; N 20.76. Found: C, 45.73; H, 4.59; N, 20.26.
From the reaction mixture was also isolated a product assigned the
structure dimethyl 5-(3-adenyl)-1,4-dioxane-2,3-dicarboxylate, 14, as a
mixture of the anomers 14a to 14b in a 1:1 ratio. Of this mixture was
observed the following spectroscopic properties. The equatorial product
14a and the axial product 14b could not be assigned in NOESY spectrum.
1H NMR (CDCl3, 400 MHz): d ¼ 8.57 (s, 1H, C2-H in adenine), 8.49 (s,
1H, C2-H in adenine), 8.04 (s, 1H, C8-H in adenine), 8.01 (s, 1H, C8-H in
adenine),d 7.5–8.5 (br., NH2), 6.71 (dd, J ¼ 8.4 Hz, 3.6 Hz, 1H, CH-
adenine), 6.42 (dd, J ¼ 9.2 Hz, 2.8 Hz, 1H, CH-adenine), 5.15 (d, J ¼ 2 Hz,
Hz, 1H, CH-COOMe), 4.87 (d, J ¼ 2 Hz, 1H, CH-COOMe), 4.77 (d,
J ¼ 9.2 Hz, 1H, CH-COOMe), 4.52 (d, J ¼ 9.2 Hz, 1H, CH-COOMe),
4.45 (dd, 1H, J ¼ 11.6 Hz, 2.8 Hz, OCH2-CH-adenine), 4.35 (dd, 1H,
J ¼ 12.4 Hz, 8.4 Hz, OCH2-CH-adenine), 4.28 (dd, 1H, J ¼ 12.4 Hz,
3.6 Hz, OCH2-CH-adenine), 4.06 (dd, 1H, J ¼ 11.6 Hz, 9.2 Hz, OCH2-
CH-adenine), 3.90, 3.87, 3.82, 3.77(s, 3H ꢂ 4, -COOCH3) ppm. 13C
NMR (CDCl3, 100 MHz): d ¼ 168.6 168.3, 167.1 166.5, 154.3, 150.8,
148.3, 148.2, 141.7, 117.2, 81.4, 78.6, 77.3, 76.3, 74.7, 73.3, 72.2, 67.6,
64.8, 59.1, 53.3, 53.2, 53.0, 52.6. IR (cmꢀ1): 3333, 3091, 2956, 1742,
1646, 1616, 1116. MS (70 eV) m=z: 337.1, 305.0, 278.1, 202.0, 149.1.
ACKNOWLEDGMENTS
We thank the Norwegian Research Council for generous financial
support.
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